NM_001291549.3:c.-141-7G>A

Variant names:

• chr6-36677689-G-A
• rs762623
• ENST00000911808.1:c.-250G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001291549.3(CDKN1A):​c.-141-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 425,748 control chromosomes in the GnomAD database, including 3,272 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1179 hom., cov: 31)
  • Exomes 𝑓: 0.12 (2093 hom.)
• Consequence: CDKN1A NM_001291549.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.889
• Publications: 33 publications found

Genes affected

CDKN1A (HGNC:1784): (cyclin dependent kinase inhibitor 1A) This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-cyclin-dependent kinase2 or -cyclin-dependent kinase4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in response to a variety of stress stimuli. This protein can interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of cyclin-dependent kinase2, and may be instrumental in the execution of apoptosis following caspase activation. Mice that lack this gene have the ability to regenerate damaged or missing tissue. Multiple alternatively spliced variants have been found for this gene. [provided by RefSeq, Sep 2015]

DINOL (HGNC:53146): (damage induced long noncoding RNA)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291549.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	NM_001291549.3		c.-141-7G>A		splice_region intron	N/A	NP_001278478.1
	CDKN1A	NM_001374509.1		c.-49-99G>A		intron	N/A	NP_001361438.1
	CDKN1A	NM_001374510.1		c.34+1119G>A		intron	N/A	NP_001361439.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN1A	ENST00000911808.1		c.-250G>A		5_prime_UTR	Exon 1 of 3	ENSP00000581867.1
	CDKN1A	ENST00000448526.6	TSL:3	c.-37-213G>A		intron	N/A	ENSP00000409259.3	P38936
	CDKN1A	ENST00000615513.4	TSL:2	c.-6+1165G>A		intron	N/A	ENSP00000482768.1	P38936

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17959 AN: 151910 Hom.: 1179 Cov.: 31

Gnomad AFR AF: 0.0924

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.118 AC: 32190 AN: 273720 Hom.: 2093 Cov.: 3 AF XY: 0.111 AC XY: 16199 AN XY: 145354

African (AFR) AF: 0.0848 AC: 694 AN: 8186

American (AMR) AF: 0.0870 AC: 1176 AN: 13514

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 1713 AN: 8766

East Asian (EAS) AF: 0.131 AC: 2328 AN: 17812

South Asian (SAS) AF: 0.0585 AC: 2562 AN: 43826

European-Finnish (FIN) AF: 0.141 AC: 1302 AN: 9258

Middle Eastern (MID) AF: 0.170 AC: 362 AN: 2130

European-Non Finnish (NFE) AF: 0.130 AC: 20195 AN: 154824

Other (OTH) AF: 0.121 AC: 1858 AN: 15404

GnomAD4 genome AF: 0.118 AC: 17967 AN: 152028 Hom.: 1179 Cov.: 31 AF XY: 0.119 AC XY: 8840 AN XY: 74272

African (AFR) AF: 0.0924 AC: 3830 AN: 41446

American (AMR) AF: 0.101 AC: 1537 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 747 AN: 3470

East Asian (EAS) AF: 0.109 AC: 563 AN: 5174

South Asian (SAS) AF: 0.0521 AC: 251 AN: 4822

European-Finnish (FIN) AF: 0.149 AC: 1566 AN: 10536

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.134 AC: 9092 AN: 67996

Other (OTH) AF: 0.117 AC: 247 AN: 2106

Alfa AF: 0.125 Hom.: 1044

Bravo AF: 0.114

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.8
DANN	Benign	0.66
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762623; hg19: chr6-36645466;